Inclusion Criteria:
* Male or female, 18 years of age or older
* Ability to understand and the willingness to sign a written informed consent document
* NDMM based on IMWG criteria with clonal bone marrow plasma cells \>10% or biopsy proven bony or extramedullary disease/plasmacytoma (EMD) with any one or more CRAB-features or myeloma defining events (Rajkumar, 2024). (See Appendix G)
* Ineligible for ASCT as assessed by the treating physician or eligible but prefers and agrees to defer ASCT until after induction and maintenance therapy, upon progression or at a later time
* Measurable disease defined as at least one of the following:
* Serum M-protein 0.5 g/dL
* Urine M-protein 200 mg/24 hours
* Serum FLC assay: involved FLC 10 mg/dL (100 mg/L) and an abnormal kappa to lambda FLC ratio (\< 0.26 or \> 1.65)
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (See Appendix A)
* Screening Laboratory evaluations with the following parameters:
* Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 109/L)
\--- Note: Growth factor support is not permitted within 10 days, \[14 days for pegfilgrastim\], prior to the screening hematologic test.
* Platelet count ≥ 75,000 cells/dL (75 x 109/L) (without transfusions required during the 3 days prior to the screening hematologic test)
* Total Bilirubin ≤ 2 X upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
* AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
* Calculated creatinine clearance (CrCl) 30ml/min (Appendix B)
* Hemoglobin ≥ 8.0 g/dl (red blood cell (RBC) transfusions are permitted)
* Individuals of childbearing potential (IOCBP) must have 2 negative pregnancy tests before initiation of therapy, and agree to ongoing testing, based on the frequency outlined in the Pregnancy Prevention Plan (PPP) (See Appendix H)
* Sexually active IOCBP agree to use protocol-specified contraceptive methods, at least 28 days prior to starting study drug, while taking study drug, including interruptions in study drugs, and for at least 28 days after the last dose of study drug or males sexually active with IOCBP, (including those who have had a vasectomy), agree to use protocol specified contraceptive methods while taking study drug, including interruptions in study drug and for at least 28 days after the last dose of iberdomide, 5 months after isatuximab and 6 months after bortezomib, according to the PPP (See Appendix H)
* All patients (male and female with or without childbearing potential) agree to counseling according to the PPP and to abstain from donating blood products for at least 28 days after the last dose of iberdomide and abstain from donating semen or sperm while taking study drug and for at least 28 days after the last dose of iberdomide according to the PPP (See Appendix H) and for 5 months after the last dose of isatuximab and 6 months after the last dose of bortezomib
* Must be able to take antithrombotic prophylaxis (See Section 5.9.1)
Exclusion Criteria:
* Prior therapy for MM. Patients may have received:
* Corticosteroids for management of MM not to exceed equivalent of 160 mg of dexamethasone in a 2-week period and should be stable 7 days prior to the registration.
* Focal palliative radiation for the management of bone pain completed ≥ 7 days prior to registration
* Treatment for smoldering myeloma as long as the prior treatment did not include anti-CD38 therapy:
* Patients with a prior history of serious allergic reactions associated with thalidomide, lenalidomide, or pomalidomide should not receive iberdomide as they could be at higher risk of hypersensitivity.
* Resolution of symptoms of prior treatment to ≤ grade 1 or baseline
* Known intolerance to steroid therapy
* Prior history of malignancies, other than MM, will be excluded unless the participant has been free of the disease for ≥ 3 years with the exception of the following non-invasive malignancies: basal or squamous cell skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological findings of prostate cancer (T1a or T1b using the Tumor, Node, Metastasis (TNM) clinical staging system), or prostate cancer that is curative
* Central nervous system involvement with MM
* Peripheral neuropathy grade 3, or grade 2 with pain on clinical exam during screening period
* Any medical or psychiatric illness that in the investigator's opinion would impose excessive risk to the patient or would adversely affect participation
* Concurrent uncontrolled cardiovascular conditions (uncontrolled hypertension, uncontrolled arrhythmias, congestive heart failure, unstable angina, grade 3 thromboembolic event or myocardial infarction) in the past 6 months
* Concurrent symptomatic amyloidosis or plasma cell leukemia
* POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
* Seropositive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B (defined as positive hepatitis B surface antigen (HepBSAg) or Hepatitis B core antibody (HepBcore Ab) or C (Hep C Ab), or acute hepatitis A. If any history of exposure to hepatitis B or C, then PCR should be negative
* Pregnant or breast feeding female or IOCBP who intend to become pregnant during the study.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to other agents used in study
